The present invention relates to novel palladium coordination complexes and their use in the treatment of animal tumors.
Recently, certain platinum complexes have been shown by Rosenberg and co-workers to be highly active anti-tumor agents (U.S. Pat. Nos. 4,177,263 and 4,140,707). For example, the complex cis-dichlorodiammine-platinum-II is the chemotherapeutic agent of choice in the treatment of many and varied tumors.
There are several drawbacks, however, associated with the use of the platinum complexes to treat tumors. Generally, the platinum complexes have a relatively low solubility in water thereby rendering it difficult to formulate a composition which can effectively deliver the reagent to the site of the tumor in the body.
Moreover, many of the platinum complexes are highly nephrotoxic thereby further restricting their use, in the absence of precautionary measures to avoid damage to the kidneys, when administered to animals afflicted with tumors.
Additionally, platinum complexes and cis-dichlorodiammine-platinum-II in particular are relatively inactive against gastro-intestinal tumors, presumably because of an inability of the complex to aquate in the presence of the high chloride concentrations found in the stomach.
It has previously been suggested to employ certain palladium complexes as anti-tumor agents in chemotherapy. However, in all instances reported in the literature the complexes tested had either little or marginal anti-tumor activity. The low activity of the palladium complexes tested heretofore, as compared with related palladium complexes, has been attributed to the fast acuation of the leaving groups which disassociate from the metal in vivo. See Connors, Cancer Treatment Reports, Vol. 63, September-October, 1979, pages 1499-1502; Lim et al, J. Inorg. Nucl. Chem., Vol. 38, pages 1911-1914 (1976); Connors, Platinum Cooridination Complexes in Cancer Chemotherapy, pages 13-37 (Springer-Verlag Berlin, 1974); Cleare, Bioinorganic Chemistry, Vol. 2, pages 187-210 (1973); Graham et al, J. Inorg, Nucl. Chem., Vol. 41, pages 1245-1249 (1979); Kirschner et al, J. Med. Chem., Vol. 9, pages 369-372 (1966); Kirschner et al, 168th Annual. Meet., ACS (September, 1974) (abstract); Kirschner et al, Adv. Exp. Med. Biol., Vol. 91, 151 (1977); Kirschner et al, Inorganic and Nutritional Aspects of Cancer, pages 151-160, Plenum, N.Y. (1978); Kirschner et al, J. Clin. Hema. and Omc., Vol. 7, page 190 (1977).
It is an object of the present invention to provide novel palladium coordination complexes having a high degree of anti-tumor activity which do not possess the disadvantageous characteristics associated with known heavy metal chemotherapeutic anti-tumor agents and with platinum complexes in particular.
It is a further object of the present invention to provide a pharmaceutical composition comprising the novel palladium complexes especially adapted for the treatment of animal tumor cells sensitive thereto.
It is a further object of the present invention to provide a therapeutic method for the treatment of animals afflicted with tumors sensitive to the novel palladium complexes.